ABSTRACT Age-related trabecular bone loss begins in young adulthood and leads to increased rates of osteoporosis and fractures in elderly men and women. It is fastest in vertebrae, where it is ~2-fold faster in women than in men, and then accelerates in post-menopausal women. Stimulation of cAMP/PKA signaling by intermittent Parathyroid Hormone-like (iPTH) drugs (teriparatide or abaloparatide) is the only FDA-approved osteoporosis therapy that acts by increasing anabolic bone formation rather than by decreasing bone resorption. However, not all patients respond, therapy is limited to 24 months, and the anabolic effects are not maintained after cessation. Moreover, iPTH therapy requires daily injection and is extremely expensive (~$30,000/year). We previously discovered that knockdown or deletion of Protein kinase inhibitor ? (Pkig) increases the anabolic processes induced by PTH/PKA in vitro. Targeting PKI? might therefore increase the magnitude of response, or the percent of patients who respond, to iPTH therapy. Because the in vivo roles of PKI? and the other two PKI family members were previously unknown, we generated Pkig-/- mice. Our preliminary results indicate that genetic deletion of Pkig overcomes both the age-related loss of bone volume and the age-related decline in skeletal healing. Our long-term goal is therefore to determine whether PKI? is a potential therapeutic target, either alone or in combination with iPTH, to overcome age-related bone loss, the age-related decline in skeletal healing, and/or post-menopausal bone loss. Our overall hypothesis is that PKI? mediates age-related bone loss and the age-related decline in skeletal healing by regulating the balance between osteogenesis and adipogenesis in a sex- and skeletal site-dependent manner. The overall hypothesis will be tested by the following Aims: Aim 1: Determine whether the effects of Pkig deletion on bone homeostasis depend on age, skeletal site, sex, and/or iPTH therapy. Aim 2: Determine mechanisms that are critical for regulation of age-related bone loss by PKI?. Aim 3: Determine whether Pkig deletion (either alone or in combination with iPTH) overcomes the age-related decline of fracture healing and/or ovariectomy (OVX)-induced bone loss.